Cannabinoid components of marijuana are known to exert behavioral and psychotropic effects but also to possess therapeutic properties including analgesia, ocular hypotension, and antiemesis. Cannabinoids-based medications are now being used for treatment of a wide range of medical conditions, including neuropathic pain, pain related to cancer and trauma, spasticity associated with multiple sclerosis, fibromyalgia, and others. This invention generally relates to treatment of symptoms associated with cannabinoid responsive diseases and disorders in subjects in need thereof, as well as the method of administering therapeutically-effective amount of a pharmaceutical compound containing cannabinoids.
The methods and compounds of the proposed invention are intended for treatment of multiple diseases and disorders such as, without limitation: autoimmune diseases and disorders, motor neuron diseases and disorders, neurodegenerative diseases and disorders, pain associated with cancer and trauma.
Other conditions are also contemplated by the invention, that include, but are not limited to: gastrointestinal, metabolic, neurological, circulatory, soft tissue, musculoskeletal, chronic or acute pain, nausea, decreased appetite, skin disorders, sexual dysfunction, glaucoma, AIDS wasting, neuropathic pain, treatment of spasticity associated with multiple sclerosis, fibromyalgia, chemotherapy-induced nausea, allergies, inflammation, infection, epilepsy, depression, migraine, bipolar disorders, anxiety disorder, dependency and withdrawal. In addition, the methods of the invention may be used to alleviate, or relief symptoms or side effects associated with anti-retroviral therapy, chemotherapy and radiation therapy. Certain diseases and disorders are briefly outlined below, and the possible mechanisms of cannabinoid action are exemplified with treatment of certain autoimmune neurodegenerative diseases.
An autoimmune disease develops when person's immune system, which defends the body against diseases starts attacking the healthy cells. An autoimmune disease can affect one or many different types of body tissue, depending on the type. It can also cause abnormal organ growth and changes in organ function. The cause of autoimmune disease is currently unknown.
There are as many as 80 types of autoimmune diseases. Many of them have similar symptoms, which makes them difficult to diagnose. It's also possible to have more than one disease at the same time. Autoimmune diseases usually fluctuate between periods of remission (few or no symptoms) and flare-ups (worsening symptoms). Currently, treatments for autoimmune diseases focused on relieving symptoms and preventing complications because there is no curative therapy. Medical interventions include: physical therapy, immunosuppressive medication, hormone replacement therapy, blood transfusions (if blood is affected), anti-inflammatory medication, pain medication, etc.
For example, multiple sclerosis (MS) is believed to be an autoimmune disease that affects the central nervous system (CNS). The CNS consists of the brain, spinal cord, and the optic nerves. Surrounding and protecting the nerve fibers of the CNS is a fatty tissue called myelin that helps nerve fibers conduct electrical impulses. In MS, myelin is lost in multiple areas, leaving scar tissue called sclerosis. These damaged areas are also known as plaques or lesions. In some cases, the nerve fiber itself is damaged or broken. When myelin or the nerve fiber is destroyed or damaged, the ability of the nerves to conduct electrical impulses to and from the brain is disrupted, and this produces the various symptoms of MS. Patients with MS can expect one of four clinical courses of disease: relapsing-remitting, primary-progressive, secondary-progressive or progressive-relapsing.
Neurodegenerative diseases, such as MS, are a group of disorders characterized by changes in normal neuronal functioning, leading, in most cases, to neuronal death. Most of these diseases are associated, especially in late stages, with severe neuronal loss. With an ever-increasing ageing population, progressively more individuals are affected by neurodegenerative diseases. According to the National Institute of Neurological Disorders and Stroke, there are more than 600 different types of neurological disorders.
Neural degeneration, or neurodegeneration, can be described as the progressive damage or death of neurons. Neurons are nerve cells in the brain whose primary function is to assist in the memory process. The damage or death of neurons leads to a gradual deterioration of the functions controlled by the affected part of the nervous system. Neural degeneration often occurs because of oxidative stress. Oxidative stress occurs to the cells when the effects of pro-oxidants (such as free radicals, reactive oxygen and reactive nitrogen species) exceed the ability of anti-oxidants to neutralize them. When levels of free radicals or other pro-oxidants increase to such an extent, they can cause damage to cell membranes which in turn may result in cell death or damage to genetic material.
Some of the most common types of neurological disorders include Alzheimer's disease, Parkinson's disease and MS. The process of neural degeneration is often the result of glutamate excitotoxicity. Glutamate is a signaling chemical and under normal conditions the concentration of glutamate in a cell tends to be quite low. Glutamate is required at these low concentrations for crucial brain functions such as memory and learning. When glutamate concentrations increase, the process of neural degeneration begins.
When the brain is deprived of oxygen either due to a disease, such as a neurogenerative disease, a trauma, such as a closed head injury or due to an ischemic event such as a stroke, an abnormal build-up of glutamate occurs. Neural degeneration takes place when glutamate attaches to receptor proteins on a cells surface. Neural degeneration continues from the destructive effects of oxidative radicals caused by the glutamate flood. The radicals cause disruption of essential reactions in the neurons and this leads to degeneration or death of the cell.
Neuroprotective agents that can block the NMDA receptor are useful as they are able to block the reaction caused by glutamate and therefore prevent neural degeneration. Some neuroprotective agents, which block the NMDA receptor, have been studied in clinical trials in stroke patients. Dextrorphan was the first NMDA antagonist to be studied in human subjects but is of limited use due to its side effects. Another drug, Selfotel, showed trends towards a higher mortality rate with patients treated with the drug rather than placebo, and as such the trials were halted. The drug Cerestat also had its trials terminated because of concerns with the benefit-to-risk ratio of the drug.
The motor neuron diseases (MNDs) are a group of progressive neurological disorders that destroy motor neurons, the cells that control essential voluntary muscle activity such as speaking, walking, breathing, and swallowing. Normally, messages from nerve cells in the brain (called upper motor neurons) are transmitted to nerve cells in the brain stem and spinal cord (called lower motor neurons) and from them to muscles. Upper motor neurons direct the lower motor neurons to produce movements such as walking or chewing. Lower motor neurons control movement in the arms, legs, chest, face, throat, and tongue.
When there are disruptions in the signals between the lowest motor neurons and the muscle, the muscles do not work properly; the muscles gradually weaken and may begin wasting away and develop uncontrollable twitching (fasciculations). After there are disruptions in the signals between the upper motor neurons and the lower motor neurons, the limb muscles develop stiffness (spasticity), movements become slow and effortful, and tendon reflexes such as knee and ankle jerks become overactive. Over time, the ability to control voluntary movement can be lost. Some MNDs are inherited, but the causes of most MNDs are not known. In sporadic or non-inherited MNDs, environmental, toxic, viral, or genetic factors may be implicated. Amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS) are among the frequently encountered MNDs.
Amyotrophic lateral sclerosis is an MND that affects over 350,000 of the world's population and kills over 100,000 every year. Early symptoms associated with ALS include tripping, dropping things, slurred or “thick” speech, and muscle cramping, stiffening, weakening, and twitching (fasciculation). In bulbar ALS, the muscles for speaking, swallowing or breathing are affected. In addition to muscle loss atrophy, the following signs of lower and upper motor neuron degeneration are often associated with ALS lower motor neuron degeneration: muscle weakness and atrophy, involuntary contraction of muscle fibers, muscle cramps, weakened reflexes, flaccidity (decreased muscle tone), difficulty swallowing, disordered articulation, shortness of breath at rest, etc. Upper motor neuron degeneration: muscle stiffness or rigidity, emotional lability (decreased ability to control emotions).
Significant advances are being made towards understanding the genetic basis for ALS as well as the mechanistic and molecular pathways mediating progression of the sporadic forms of the disease, however, effective pharmacotherapy remains elusive. Two of the primary theories underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage.
The use of cannabis as a medicine has long been known and during the 19th century preparations of cannabis were recommended as a hypnotic sedative which were useful for the treatment of hysteria, delirium, epilepsy, nervous insomnia, migraine, pain and dysmenorrhea. Until recently the administration of cannabis to a patient was mainly achieved by preparation of cannabis by decoction in ethanol, which could then be swallowed or by the patient inhaling the vapors of cannabis by smoking the dried plant material.
Recent methods have sought to find new ways to deliver cannabinoids to a patient including those which bypass the stomach and the associated first pass effect of the liver which can remove up to 90% of the active ingested dose and avoid the patient having to inhale unhealthy tars and associated carcinogens into their lungs. Such dosage forms include administering the cannabinoids to the sublingual or buccal mucosae, inhalation of a cannabinoid vapor by vaporization or nebulization, enemas or solid dosage forms such as gels, capsules, tablets, pastilles and lozenges.
Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals, these are termed endocannabinoids. Synthetic cannabinoids are chemicals with similar structures to plant cannabinoids or endocannabinoids. Plant cannabinoids can also be isolated such that they are “essentially pure” compounds. These isolated cannabinoids are essentially free of the other naturally occurring compounds, such as, other minor cannabinoids and molecules such as terpenes.
The U.S. Pat. No. 7,449,589, referenced herein, demonstrates one of many processes for purifying (−)-Δ9-trans-tetrahydrocannabinol and shows various cannabinoid compounds, including THC, CBD, and CBN. The THC reportedly has at least eight individual isomers of which (−)-Δ9-trans-tetrahydrocannabinol ((−)-Δ9-trans-THC) is the main and most active isomer. Although A8-tetrahydrocannabinol has similar activity as (−)-Δ9-trans-THC, it is only approximately 75% as potent and also tends to degrade to other compounds including CBN. (U.S. Pat. No. 7,449,589 B2, 2004)
Essentially pure compounds have a degree of purity up to at least 95% by total weight. Some essentially pure cannabinoids (whether synthetic or isolated) have been suggested to be neuroprotective agents, either by direct antagonism of the NMDA receptor or by reducing the influx of calcium ions into the cell by another means such as binding with cannabinoid receptors. Clearly there is a significant requirement for an efficacious NMDA antagonist to prevent or treat neural degeneration.
It was discovered that glutamate toxicity could be prevented to some extent by isolated or synthetic tetrahydrocannabinol (THC) or cannabidiol (CBD). (Hampson, Grimaldi, Axelrod, & Wink, 1998) The cannabinoids were tested in vitro on neuronal cultures exposed to glutamate. Cannabidiol (CBD) and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate.
According to one study, the psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD), a non-psychoactive constituent of marijuana, both reduced NMDA, AMPA and kainate receptor mediated neurotoxicity. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. (Hampson, et al., 2000)
Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction-based system, it was demonstrated that cannabidiol (CBD), THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as antioxidants in neuronal cultures, cannabidiol (CBD) was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol (CBD) may be at least as effective in vivo as seen in these in vitro studies. (Hampson, et al., 2000)
The example illustrated in the FIG. 2, incorporated herein by reference, compares the oxidation potentials of cannabinoids and the antioxidant butylated hydroxytoluene (BHT). Effect of cannabidiol and THC on dihydrorhodamine oxidation. Cannabinoids were compared with BHT for their ability to prevent tert-butyl hydroperoxide-induced oxidation of dihydrorhodamine. This experiment was repeated four times with essentially the same results. (Hampson, Grimaldi, Axelrod, & Wink, 1998)
In 1988 a study was undertaken to determine the analgesic and anti-inflammatory activity of various cannabinoids and cannabinoid pre-cursors. Oral administration of CBD was found to be the most effective at inhibition of PBQ-induced writhing in mice. THC and cannabinol (CBN) were found to be least effective at reducing analgesia and inflammation. (Formukong, Evans, & Evans, 1988) Another study undertaken in 1998, as demonstrated in the FIG. 1, incorporated herein by reference, compares the oxidation potentials of cannabinoids and the antioxidant butylated hydroxytoluene (BHT).
Further, certain anecdotic evidence suggests that cannabinoid-containing plant extracts are demonstrating higher efficacy in treatment of some neurodegenerative diseases than essentially pure cannabinoids. Specifically, cannabinoid-containing plant extracts comprising, as a predominant cannabinoid, tetrahydrocannabinol (THC) and cannabidiol (CBD)—particularly effective in the retardation of neural degeneration.
Several pharmaceutical products exist which contain either phytocannabinoids (natural) or synthetic cannabinoids. For example, dronabinol (Marinol) is the International Nonproprietary Name (INN) for an encapsulated THC product which has been used therapeutically as an appetite stimulant, antiemetic, and analgesic, either as an inhalant or as an oral drug. Also, nabilone (Cesamet) is a synthetic analog of dronabinol (Marinol), while Sativex is a cannabinoid extract oral spray containing THC, and other cannabinoids that are used to treat neuropathic pain and spasticity. Further, rimonabant (marketed under various tradenames) is a selective cannabinoid receptor antagonist used as an anti-obesity drug and as a smoking cessation. Several other cannabinoid-containing products exist.
Thus, considering the therapeutic effect of compounds containing cannabinoids, especially (−)-Δ9-trans-THC, there is a continuing need for improving existing cannabinoid-containing products as well as a need for new products containing cannabinoids, especially in the pharmaceutical field.
The U.S. Pat. No. 8,628,796, referenced herein, discloses an encapsulated THC composition, including (−)-Δ9-trans-THC purportedly having improved stability. The disclosure emphasizes that the stability can be improved by including bases (e.g., amines) in the formulation. In addition, the stability of the compositions disclosed is best preserved by storing the compositions in a sealed container, such as in a capsule, and under refrigerated conditions. Specifically, the disclosure asserts that one embodiment of the invention described therein overcomes the deficiencies of prior art oral dosage forms containing (−)-Δ9-trans-THC by utilizing hard gelatin capsules, instead of soft gelatin capsules. As stated in the disclosure, unlike soft gelatin capsules, hard gelatin capsules do not contain glycerol—a major cause of instability for the active (−)-Δ9-trans-THC pharmaceutical ingredient. The disclosure purports to provide a stable product, such as one that does not degrade to an unacceptable extent during the desired shelf-life of the dosage form. (U.S. Pat. No. 8,628,796 B2, 2005)
The U.S. Pat. No. 7,968,594, referenced herein, discloses the invention that relates to treatment of cancer related pain and constipation. The subject in need is administered a combination of the cannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in a predefined ratio by weight of approximately 1:1 of CBD to THC. (U.S. Pat. No. 7,968,594 B2, 2005)
The U.S. Pat. No. 9,205,063, referenced herein, discloses the invention that relates to the use of cannabinoid-containing plant extracts in the prevention or treatment of neural degeneration. Specifically, the invention relates to use of one or more cannabinoid-containing plant extracts in the prevention or treatment of neural degeneration, wherein the one or more cannabinoid-containing plant extracts comprise a cannabinoid-containing fraction and a non-cannabinoid containing fraction. (U.S. Pat. No. 9,205,063 B2, 2014)
The U.S. Pat. Application No. 20,140,228,438, referenced herein, discloses the invention that relates to cannabinoids for use in the prevention or treatment of neurodegenerative diseases or disorders. Preferably, the cannabinoids are cannabichromene (CBC) cannabidivarin (CBDV) and/or cannabidivarin acid (CBDVA). More preferably, the neurodegenerative disease or disorder to be prevented or treated is Alzheimer's disease. (US Patent No. US20140228438 A1, 2012)
The U.S. Pat. Application No. 20,060,135,599, referenced herein, discloses the invention that relates to the use of one or more cannabinoids in the treatment of neuropathic or chronic pain. A method of treating brachial plexus avulsion in a human patient comprising administering to a patient in need thereof effective amount one or more cannabinoids. (US Patent No. US20060135599 A1, 2003)
The U.S. Pat. No. 8,980,940, referenced herein, discloses a composition comprising a high purity cannabinoid, an acid, and a pharmaceutically-acceptable solvent that achieves room temperature stability for over 24 months. The acid improves the stability of the composition and the solvent enhances the solubility of the acid, thereby allowing the acid to have an improved stabilizing effect on the highly pure cannabinoid. Preferably, the solvent is an alcohol and, more preferably, the composition contains an oil. A method for making the composition includes combining the cannabinoid and the solvent and evaporating a portion of the solvent, along with adding an acid to the composition, before, during, or after the evaporating step. A method for making and storing the composition includes storing the composition in a manner adapted to maintain its stability. (U.S. Pat. No. 8,980,940 B2, 2011)
The U.S. Pat. Application No. 20,080,175,902, referenced herein, discloses methods for slowing the progression of multiple sclerosis comprising administering a therapeutically effective amount of a cannabinoid to a patient suffering from multiple sclerosis. A method of slowing the progression of multiple sclerosis in a patient in need thereof, comprising administration of a pharmaceutical composition containing an effective amount of therapeutically effective cannabinoid on a regular basis; the administration occurring over a period of time: at least about 16 weeks, at least about 27 weeks, at least about 40 weeks and at least about 52 weeks. (US Patent No. US20080175902 A1, 2007)
The U.S. Pat. Application No. 20,060,167,084, referenced herein, discloses methods of, inter alia, treating and/or preventing symptoms associated with multiple sclerosis and its relapse. A method of treating and/or preventing symptoms associated with multiple sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising delta-9-tetrahydrocannabinol. (US Patent No. US20060167084 A1, 2005)
The U.S. Pat. Application No. 20,040,018,151, referenced herein, discloses in one aspect, a method for promoting normal motor function in ALS patients. The method comprises administering a compound that is an anandamide/cannabinoid receptor/acceptor agonist to a mammal having observable motor function and evaluating one or more indicia of motor function in said mammal, wherein a compound that promotes normal motor function is identified. More preferably, the mammal to which the administration is made has one or more ALS or MND symptoms and such one or more symptoms include at least one of the observable motor functions being evaluated. (US Patent No. US20040018151 A1, 2003)